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Pediatric ALK-positive anaplastic large cell lymphoma is a rare subtype of non-Hodgkin lymphoma, and approximately 30% of patients relapse following treatment with conventional chemotherapy. Alectinib monotherapy has demonstrated excellent activity in relapsed and refractory ALCL, but its role as a maintenance therapy after hematopoietic cell transplantation is unclear. We experienced a relapse case of pediatric ALK-positive ALCL with central nervous system involvement treated with alectinib maintenance therapy following cord blood transplantation. The patient has maintained complete remission for more than 3 years after transplantation. There were no remarkable adverse effects that led to discontinuation of alectinib. [ABSTRACT FROM AUTHOR]

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin's lymphoma Berlin–Frankfurt–Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% (95% confidence interval [CI], 69.0% to 83.9%) and 92.3% (95% CI, 86.1% to 95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5% to 95.5%), and 67.9% (95% CI, 55.4% to 77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6% to 19.0%), 65.7% (95% CI, 47.6% to 78.9%), 55.7% (95% CI, 26.2% to 77.5%), and 70.7% (95% CI, 48.6% to 84.6%), respectively. At the end of follow-up, one of the five patients who received maintenance therapy with VBL relapsed, and seven patients receiving anaplastic lymphoma kinase inhibitor maintenance therapy did not experience relapse. Conclusion: This study has confirmed the poor prognostic of MDD (+), high-risk site and SC/LH, but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305). [ABSTRACT FROM AUTHOR]

Purpose of Review: This review aims to provide a comprehensive overview of the current understanding of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), including its incidence, risk factors, clinical presentation, and diagnostic criteria. The aim is to enhance awareness among healthcare professionals and patients about BIA-ALCL, its management strategies, and the importance of surveillance in individuals with breast implants. Recent Findings: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T cell lymphoma characterized by the presence of the CD30 biomarker. Although BIA-ALCL is more prevalent than other primary breast lymphomas, its incidence rate is extremely low. Textured implants have been associated with nearly all instances of BIA-ALCL. A significant proportion of BIA-ALCL patients exhibit an excellent prognosis after the extraction of the implants and capsules. Unfavorable outcomes are seen in instances of tumor bulk and implant capsule invasion. Summary: This review provides an in-depth understanding of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), focusing on its incidence, risk factors, clinical presentation, diagnostic criteria, and imaging evaluation. BIA-ALCL management techniques, treatment modalities, effectiveness, and outcomes are examined to improve patient care and awareness. [ABSTRACT FROM AUTHOR]

Anaplastic Large Cell Lymphoma (ALCL) is an uncommon type of Non Hodgkin Lymphoma (NHL). It commonly arises in lymph nodes and can also involve extranodal sites such as the skin, soft tissues, lungs, bones, and liver. Here, a case of Anaplastic Lymphoma Kinase (ALK)-positive ALCL in a 17-year-old male patient who presented with swelling in the frontal and occipital bones is presented. The patient was clinically and radiologically diagnosed with Langerhans Cell Histiocytosis (LCH), and excision of the occipital lesion was performed. Preoperatively, lymphoma was not considered a differential diagnosis. Detailed histopathological examination, immunohistochemistry, and Positron Emission Tomography (PET) scan confirmed the diagnosis of primary bone ALK-positive ALCL. This T-cell NHL is composed of large lymphoid cells with abundant cytoplasm and pleomorphic horseshoe or kidney-shaped nuclei, with characteristic ALK and CD30 positivity. An isolated presentation of ALCL as a primary lesion in the bone is extremely rare. Clinicians and pathologists should be aware of this rare presentation, as prompt diagnosis and proper treatment can lead to favourable outcomes.

Background: Previous studies have shown that at least a of intraoral eosinophilic ulcer is best classified as a CD30 + T-cell lymphoproliferative disorder (LPD), with histopathology reminiscent of lymphomatoid papulosis (LyP) of the skin. Microscopically, a mixed population of inflammatory cells, often including eosinophils and varying numbers of atypical lymphoid cells, frequently expressing CD30, is typical for LyP, whose clinicopathological spectrum includes type A, B, C, D, E, and LyP with DUSP22/IRF4 rearrangement. To date, about 27 intraoral LyP cases have been reported. Of them, 7 cases were diagnosed as LyP type C, which is frequently confused with anaplastic large cell lymphoma (ALCL) on histopathology. Methods: A 60-year-old male was referred for a one-month history of a tongue ulcer. Results: Microscopy showed numerous subepithelial atypical large lymphoid cells, which expressed CD4 (with partial loss of CD3, CD5, and CD7), CD8 (few cells), CD30 (about 50%, in non-diffuse pattern with size variability), TIA-1, and Ki-67 (85%), without staining for CD56, ALK, LMP1, and EBER1/2, concerning for a diagnosis of ALCL. However, after three weeks, the lesion completely healed. Conclusion: We present here a rare case of intraoral CD30+ T-cell LPD that we believe is the oral counterpart of cutaneous LyP type C. [ABSTRACT FROM AUTHOR]

EBV-positive nodal T- and NK-cell lymphoma (EBV+ NT/NKCL) is a recently recognized entity in the 5th edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Notably, CD30 positivity is frequently observed in (EBV+ NT/NKCL), creating diagnostic challenges to distinguish it from ALK-negative anaplastic large cell lymphoma (ALCL). Furthermore, cases of EBV+ ALCL have been documented in the literature, predating the inclusion of EBV+ nodal cytotoxic T-cell lymphoma as a variant of peripheral T-cell lymphoma. We present a case of a 47-year-old male presenting with multiple lymphadenopathies. The histomorphologic and immunophenotypic features of the lymph node closely resemble ALK-negative ALCL, characterized by uniform CD30 expression and a subcapsular distribution of lymphoma cells. However, the lymphoma cells exhibit diffuse positivity for EBV, consistent with EBV+ NT/NKCL. A case of ALK-negative ALCL with an immunophenotype identical to the EBV-positive case is included for comparison. Given that EBV+ NT/NKCL represents an aggressive neoplasm requiring unique clinical management compared to ALK-negative ALCL, it is critical to accurately differentiate EBV+ NT/NKCL from ALK-negative ALCL with a cytotoxic T-cell immunophenotype. [ABSTRACT FROM AUTHOR]

Anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) are rare cancers observed predominantly in children and young adults. ALCL accounts for 10–15% of all pediatric non-Hodgkin lymphomas and is commonly diagnosed at an advanced stage of disease. In children, 84–91% of cases of ALCL harbor an anaplastic lymphoma kinase (ALK) gene translocation. IMT is a rare mesenchymal neoplasm that also tends to occur in children and adolescents. Approximately 50–70% of IMT cases involve rearrangements in the ALK gene. A combination of chemotherapeutic drugs is typically used for children with ALK-positive ALCL, and the only known curative therapy for ALK-positive IMT is complete surgical resection. Crizotinib, a first-generation ALK inhibitor, was approved in the USA in 2021 for pediatric patients and young adults with relapsed or refractory ALK-positive ALCL; however, its safety and efficacy have not been established in older adults. In 2022, crizotinib was approved for adult and pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT. This podcast provides an overview of ALK-positive ALCL and IMT. We discuss the current treatment landscape, the role of ALK tyrosine kinase inhibitors, and areas of future research. [ABSTRACT FROM AUTHOR]

Anaplastic Large Cell Lymphoma (ALCL) is an uncommon type of Non Hodgkin Lymphoma (NHL). It commonly arises in lymph nodes and can also involve extranodal sites such as the skin, soft tissues, lungs, bones, and liver. Here, a case of Anaplastic Lymphoma Kinase (ALK)-positive ALCL in a 17-year-old male patient who presented with swelling in the frontal and occipital bones is presented. The patient was clinically and radiologically diagnosed with Langerhans Cell Histiocytosis (LCH), and excision of the occipital lesion was performed. Preoperatively, lymphoma was not considered a differential diagnosis. Detailed histopathological examination, immunohistochemistry, and Positron Emission Tomography (PET) scan confirmed the diagnosis of primary bone ALK-positive ALCL. This T-cell NHL is composed of large lymphoid cells with abundant cytoplasm and pleomorphic horseshoe or kidney-shaped nuclei, with characteristic ALK and CD30 positivity. An isolated presentation of ALCL as a primary lesion in the bone is extremely rare. Clinicians and pathologists should be aware of this rare presentation, as prompt diagnosis and proper treatment can lead to favourable outcomes. [ABSTRACT FROM AUTHOR]

Non-Hodgkin lymphomas are malignant tumor that arises from the lymphoreticular system. Anaplastic large cell lymphoma (ALCL) is a type of non-Hodgkin lymphoma distinguished by the proliferation of pleomorphic large lymphoid cells expressing CD30 antigen. This case report is about a 55-year-old patient who had pain and swelling in her lower front teeth region. The immunohistochemistry report confirmed the diagnosis of high-grade non-Hodgkin’s lymphoma of the anaplastic null cell type.

EBV-positive nodal T- and NK-cell lymphoma (EBV+ NT/NKCL) is a recently recognized entity in the 5th edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Notably, CD30 positivity is frequently observed in (EBV+ NT/NKCL), creating diagnostic challenges to distinguish it from ALK-negative anaplastic large cell lymphoma (ALCL). Furthermore, cases of EBV+ ALCL have been documented in the literature, predating the inclusion of EBV+ nodal cytotoxic T-cell lymphoma as a variant of peripheral T-cell lymphoma. We present a case of a 47-year-old male presenting with multiple lymphadenopathies. The histomorphologic and immunophenotypic features of the lymph node closely resemble ALK-negative ALCL, characterized by uniform CD30 expression and a subcapsular distribution of lymphoma cells. However, the lymphoma cells exhibit diffuse positivity for EBV, consistent with EBV+ NT/NKCL. A case of ALK-negative ALCL with an immunophenotype identical to the EBV-positive case is included for comparison. Given that EBV+ NT/NKCL represents an aggressive neoplasm requiring unique clinical management compared to ALK-negative ALCL, it is critical to accurately differentiate EBV+ NT/NKCL from ALK-negative ALCL with a cytotoxic T-cell immunophenotype.

Abstract Anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) are rare cancers observed predominantly in children and young adults. ALCL accounts for 10–15% of all pediatric non-Hodgkin lymphomas and is commonly diagnosed at an advanced stage of disease. In children, 84–91% of cases of ALCL harbor an anaplastic lymphoma kinase (ALK) gene translocation. IMT is a rare mesenchymal neoplasm that also tends to occur in children and adolescents. Approximately 50–70% of IMT cases involve rearrangements in the ALK gene. A combination of chemotherapeutic drugs is typically used for children with ALK-positive ALCL, and the only known curative therapy for ALK-positive IMT is complete surgical resection. Crizotinib, a first-generation ALK inhibitor, was approved in the USA in 2021 for pediatric patients and young adults with relapsed or refractory ALK-positive ALCL; however, its safety and efficacy have not been established in older adults. In 2022, crizotinib was approved for adult and pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT. This podcast provides an overview of ALK-positive ALCL and IMT. We discuss the current treatment landscape, the role of ALK tyrosine kinase inhibitors, and areas of future research.

Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of anaplastic large cell lymphoma (ALCL). We identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 9 (AMX6001) showed better in vitro activity against ALK and NPM-ALK kinase and significantly inhibited proliferation of Karpas299 and SU-DHL-1 cell lines. In vivo efficacy of compound 9 was better than reference standard ceritinib in ALCL Karpas299 mice models. Daily oral treatment of compound 9 (25 mg/kg) induced tumor suppression TGI up to 95.8 % in ALCL models.

We report a case of primary pulmonary anaplastic lymphoma kinase-positive anaplastic large cell lymphoma in a 38-year-old woman with a smoking and vaping history. The patient presented with hypoxemia and a history of shortness of breath, cough, and intermittent fevers. Initial imaging and pleural fluid studies suggested possible empyema. Despite being given antibiotics, her respiratory status continued to deteriorate and she was put on extracorporeal membrane oxygenation. Repeat imaging showed increased size of intrathoracic lymph nodes and perilymphatic pulmonary nodules. IV steroids were initiated after bronchoalveolar lavage revealed lipophages suggestive of e-cigarette, or vaping, product use-associated lung injury. A laboratory workup revealed no signs of rheumatologic disease, and negative cultures ruled out a bacterial or fungal cause of the disease. Because of these laboratory results and because the patient did not show clinical signs of improvement, a biopsy of the left lower lobe lymph node was performed. The patient was diagnosed with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma based on the results of the biopsy. This case highlights the importance of suspecting pulmonary lymphoma in patients with a history of B-symptoms and compatible imaging findings, despite its rarity.

Summary: Peripheral T‐cell lymphomas (PTCL) are morphologically and biologically heterogeneous and a subset expresses CD30, including anaplastic large cell lymphomas (ALCL) and a minority of PTCL, not otherwise specified (PTCL, NOS). ALCL with ALK translocations (ALCL, ALK+) are readily identified by routine diagnostic methods, but differentiating ALCL without ALK translocation (ALCL, ALK−) and PTCL, NOS expressing CD30 (PTCL CD30+) can be challenging. Furthermore, rare PTCL co‐express CD30 and CD15 (PTCL CD30+CD15+); some resemble ALCL, ALK− while others resemble classic Hodgkin lymphoma. To explore the relationship between PTCL CD30+CD15+ and ALCL, ALK−, we analysed 19 cases of PTCL with CD30 expression, previously diagnosed as ALCL, ALK− (nine cases) and PTCL CD30+CD15+ (10 cases) for DUSP22/IRF4 rearrangements, coding RNA expression and selected transcriptome analysis using the NanoString nCounter gene expression analysis platform. Unsupervised clustering showed no clear segregation between ALCL, ALK− and PTCL CD30+CD15+. Three cases previously classified as PTCL CD30+CD15+ showed DUSP22/IRF4 rearrangements, favouring a diagnosis of ALCL, ALK−. Our results suggest that cases previously designated PTCL CD30+CD15+, likely fall within the spectrum of ALCL, ALK−; additionally, a subset of ALCL, ALK− with DUSP22/IRF4 rearrangement expresses CD15, consistent with previous reports and expands the immunophenotypic spectrum of this lymphoma subgroup. [ABSTRACT FROM AUTHOR]

Brentuximab vedotin (BV), CD30 specific antibody drug conjugate, has been used to treat anaplastic large cell lymphoma (ALCL) and classic Hodgkin lymphoma (CHL); it is also used in the treatment of other CD30-positive peripheral T-cell lymphomas. We aimed to investigate the incidence and clinicopathological characteristics of patients with ALCL or CHL with loss of or decrease in CD30 expression after BV-containing therapy. Twelve and nine patients with refractory/relapsed CHL and ALCL, respectively, were analyzed after receiving BV-containing therapy. In four ALCL patients (44%), CD30 expression was lost/decreased in re-biopsy materials, including one with complete loss and three with a reduction of less than 20%. All 12 CHL patients showed consistent CD30 expression levels after BV treatment. Compared with five ALCL patients with consistent CD30 expression, four ALCL patients with a loss of/decrease in CD30 expression received a higher cumulative dose of BV (P = 0.014) and revealed a lower intensity of CD30 expression in initial biopsy materials (P = 0.017). The subtypes of ALCL (ALK positive, ALK negative, and primary cutaneous) were not related to the loss of/decrease in CD30 expression. In conclusion, 44% of ALCL patients, regardless of histological subtypes, showed a loss of/decrease in CD30 expression after receiving BV-containing therapy, but this phenomenon was not observed in CHL patients. A higher cumulative dose of BV and a lower amount of CD30 antigen in tumor cells in the initial biopsy materials might be predictors of a loss of/decrease in CD30 expression in ALCL patients. [ABSTRACT FROM AUTHOR]

T-cell lymphoma is an extremely rare form of malignancy in the female genital tract. Most of the reported cases of lymphoma are B-cell lymphomas. A few cases of primary T-cell lymphomas involving the vagina or the vulva have been reported. We are reporting the first case of anaplastic large cell lymphoma (ALCL) presenting as a uterine cervical mass. The patient is a 24-year-old female who presented to the emergency room with a history of menorrhagia, night sweats and 40-pound weight loss. The diagnosis of ALCL was confirmed through immunohistochemical studies with strong CD30 and ALK expression. Fluorescent hybridization showed a rearrangement of the anaplastic lymphoma kinase (ALK) gene. Since ALCL may have a variable expression of T-cell antigens, the diagnosis may easily be missed when CD45 and/or CD3 is negative, and screening epithelial stains for carcinoma (e.g., p63 and EMA) are positive. CD30 must be performed to raise the consideration of ALCL when reniform nuclei are observed. [ABSTRACT FROM AUTHOR]

Primary central nervous system (CNS) ALK-negative anaplastic large cell lymphoma (ALCL) is a rare and enigmatic disease, with limited data available in the literature. This case report adds to the existing body of knowledge by describing a unique case of a 68-year-old, immunocompetent male who presented with a single ring-enhancing lesion, which upon further analysis proved to be an ALK-negative ALCL that was primary to the CNS. A comprehensive review of the existing literature is provided, highlighting the genetic characteristics and diverse neuroimaging findings of this disease entity. This report adds valuable information to the understanding of this rare disorder, and highlights the need for further research in the field of primary CNS ALK-negative ALCL.

Background: Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. The prognosis of patients with relapsed or refractory ALCL following first-line chemotherapy is extremely poor. NCCN guidelines recommend intensified chemotherapy with or without ASCT consolidation for r/r ALCL, however, this is not an effective treatment for all ALK+ALCL. Case report: Herein, we report a patient with relapsed/refractory ALK+ ALCL who received crizotinib and brentuximab vedotin as bridging therapy, followed by autologous stem cell transplantation and sequential anti-CD30 CAR T cell therapy. Conclusion: The patient achieved complete remission and long-term disease-free survival of months and continues to be followed up. The combination therapy model in this case may provide guidance for the management of relapsed/refractory ALK+ ALCL, and further prospective trials are needed to confirm its effectiveness. [ABSTRACT FROM AUTHOR]

One of the most common subgroups of cutaneous T-cell lymphomas is that of primary cutaneous CD30-positive lymphoproliferative disorders. The group includes lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL), as well as some borderline cases. Recently, significant progress has been made in understanding the genetics and treatment of these disorders. This review article summarises the clinical evidence supporting the current treatment options for these diseases. Recent years have seen the introduction of novel agents into clinical practice; most of these target CD30, such as anti-CD30 monoclonal antibodies and conjugated antibodies (brentuximab vedotin), bispecific antibodies and cellular therapies, particularly anti-CD30 CAR-T cells. This paper briefly reviews the biology of CD30 that makes it a good therapeutic target and describes the anti-CD30 therapies that have emerged to date. [ABSTRACT FROM AUTHOR]

Following the results of the CROWN phase III trial, the third-generation macrocyclic ALK inhibitor lorlatinib has been introduced as a salvage option after the failure of a first-line TKI in ALK-rearranged NSCLC, while its precise role in the therapeutic algorithm of ROS1 positive disease is still to be completely defined. The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood–brain barrier penetration are the reasons for the growing popularity and interest in this molecule. Nevertheless, the major vulnerability of this drug resides in a peculiar profile of related collateral events, with neurological impairment being the most conflicting and debated clinical issue. The cognitive safety concern, the susceptibility to heterogeneous resistance pathways, and the absence of a valid alternative in the second line are strongly jeopardizing a potential paradigm shift in this oncogene-addicted disease. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses. [ABSTRACT FROM AUTHOR]

A case of cytoplasmic anaplastic lymphoma kinase (ALK)‐positive anaplastic large cell lymphoma (ALCL) initially involving the skin in a 44‐year‐old Japanese female is reported. The patient had a hemorrhagic erythematous tumor on the right thigh without any systemic symptoms. Pathology showed diffuse infiltration of CD30‐positive anaplastic large cells positive for epithelial membrane antigen and cytoplasmic ALK. The right inguinal lymph node showed infiltration of tumor cells in the marginal sinus. Only 2 weeks after radiation therapy, the patient developed multiple subcutaneous nodules and lung involvement. Even after subsequent multichemotherapy sessions, cutaneous recurrence occurred. Literature review of cytoplasmic ALK‐positive ALCL initially involving in the skin revealed that skin lesions were mostly seen in the extremities and that half of the cases developed extracutaneous lesions. Radiation and chemotherapy were effective for most cases. Inverse RT‐PCR identified a tumor necrosis factor receptor‐associated factor (TRAF)1‐ALK fusion in our case. Most reported cases with this translocation experienced repeated changes in chemotherapy, suggesting poorer prognosis. Although ALK‐positive ALCL generally responds well to chemotherapy, the presence of a TRAF1‐ALK fusion may suggest resistance to treatment. Detection of fusion partners of ALK is important for predicting clinical courses and deciding treatment options. [ABSTRACT FROM AUTHOR]

Simple Summary: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Approximately 30% of patients treated with conventional chemotherapy experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL, such as the morphological pattern of the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL requires salvage therapy. Recently, targeted therapies such as ALK inhibitors and brentuximab vedotin have demonstrated dramatic responses in chemoresistant ALK-positive ALCL. Hematopoietic stem cell transplantation has also been reported to be an effective therapy. This article reviews pediatric ALK-positive ALCL, focusing on the risk factors associated with poor prognosis and treatment strategies for relapsed or refractory disease. Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody–drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL. [ABSTRACT FROM AUTHOR]

Heuristics are cognitive strategies used to facilitate decision‐making. They can be helpful tools for expediting pathologic diagnoses, however, they can also affect judgment and lead to biases that guide the pathologist astray. We report the case of a 52‐year‐old female who presented with two unusual pigmented lesions on the wrist and thigh that clinically and histopathologically resembled an atypical melanocytic proliferation. A biopsy of the thigh revealed a broad proliferation of large, atypical cells forming nests within a heavily pigmented epidermis. The lesion was initially misdiagnosed as melanoma in situ, despite equivocal staining for melanocytic markers, likely due to anchoring and adjustment as well as availability biases, which restricted the differential diagnosis and limited the selection of immunohistochemical stains. It was later discovered through chart review that the patient had a prior history of a cutaneous CD30+ lymphoproliferative disorder, which eventually led to the appropriate diagnosis in this case. Herein, we highlight a rare and unusual presentation of a pigmented epidermotropic CD30+ lymphoproliferative disorder, along with the biases leading to its misdiagnosis and the steps leading to the revelation of the actual diagnosis. [ABSTRACT FROM AUTHOR]

Anaplastic large cell lymphomas (ALCL) are mature T-cell neoplasms, approximately half of which harbor rearrangements of the ALK gene that confer a good prognosis. Recent studies have demonstrated that a significant proportion of ALK-negative ALCLs demonstrate rearrangements of the IRF4/DUSP22 locus that also are typically associated with a favorable prognosis. ALCL with primary involvement of the central nervous system (CNS) is extremely rare. We report what may be the first case of ALK-negative ALCL with IRF4/DUSP22 rearrangement involving the brain in a 55-year-old man. Magnetic resonance imaging demonstrated signal abnormalities in the periventricular region, corpus callosum and cingulate gyrus. Biopsy revealed a diffuse parenchymal and angiocentric infiltrate of CD30-positive cells that showed IRF4/DUSP22 rearrangement by fluorescence in situ hybridization. We also review the clinical and pathologic features of primary CNS ALK-negative ALCLs in the literature and highlight the need for awareness of this entity to optimize appropriate management.

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Background: Anaplastic lymphoma kinase-positive (ALK+) large cell lymphoma (ALCL) is a systemic lymphoma. The invasion of the head and neck bone and skin by ALK+ ALCL is relatively uncommon in children. Methods: We describe a 13-year-old boy diagnosed with ALK+ ALCL. Results: He went a surgery of sampling biopsy procedure. Then the boy was treated with six cycles of adjuvant chemotherapy with Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Munster (NHL-BFM)-90 K3 arm. Then, he achieved partial remission (PR). Conclusions: It is common for children to develop ALCL, which grows rapidly. Therefore, a sampling biopsy procedure and NHL-BFM-90 K3 were necessary for the patient. [ABSTRACT FROM AUTHOR]

Anaplastic large cell lymphoma (ALCL) with leukaemic presentation (either ab initio or along the course of the disease) has been rarely reported. Irrespective of ALK expression in the neoplastic cells, it features a dismal prognosis. We report a rare case of leukaemic, small cell variant ALK-positive ALCL with 9-year survival in a young woman who was treated upfront with corticosteroids and standard chemotherapy, and review thoroughly the previously published cases. Such an unexpected, good outcome hints at the existence of different clinical subgroups in the leukaemic variant of ALK-positive ALCL. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) at diagnosis is rare and leads to poor prognosis with the use of the standard ALCL99 protocol alone. CNS-directed intensive chemotherapy, such as an increased dose of intravenous MTX, increased dose of dexamethasone, intensified intrathecal therapy, and high-dose cytarabine, followed by cranial irradiation, has been shown to improve survival in this population. In this paper, the authors describe a 14-year-old male with an intracranial ALCL mass at onset who received CNS-directed chemotherapy followed by 23.4 Gy of whole-brain irradiation. After the first systemic relapse, the CNS-penetrating ALK inhibitor, alectinib, was applied; it has successfully maintained remission for 18 months without any adverse events. CNS-penetrating ALK inhibitor therapy might prevent CNS relapse in pediatric ALK-positive ALCL. Next-generation ALK inhibitors could be introduced as a promising treatment option, even for primary ALCL with CNS involvement, which could lead to the omission of cranial irradiation and avoid radiation-induced sequalae. Further evidence of CNS-penetrating ALK inhibitor combined therapy for primary ALK-positive ALCL is warranted to reduce radiation-induced sequalae in future treatments.

Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin’s lymphoma (NHL) in children, accounting for 10–15% of all NHL cases. ALCL is currently classified as follows: systemic anaplastic lymphoma kinase (ALK)-positive, systemic ALK-negative, primary cutaneous, and breast implant-associated ALCL. In children, systemic ALK-positive ALCL is the most common, and patients often present with extranodal involvement. We report a rare case of systemic ALK-positive ALCL with primary bone involvement in a 15-year-old male patient. Primary bone lymphoma is most commonly observed in diffuse large B-cell lymphoma and is extremely rare in systemic ALCL. Therefore, the clinical features and prognosis of primary bone ALCL remain unclear. Our patient had spontaneous remission of primary maxillary bone ALCL after gingival scraping but relapsed 12 months later with rib metastasis. Spontaneous remission of ALCL has been reported frequently in primary cutaneous ALCL and rarely in systemic ALCL. Our case demonstrates for the first time that systemic ALCL can also present as solitary bone involvement that can spontaneously remit. Because systemic ALCL is aggressive and has a risk of relapse, as in our case, it is important to consider ALCL in the differential diagnosis of primary bone lesions and to make a precise pathological diagnosis.

Abstract Approximately one‐third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high‐risk patients. The introduction of novel therapeutic modalities is much needed for these sub‐group patients. Two groups (n = 3, n = 4) of ALCL patients were treated with crizotinib‐ and alectinib‐included ALCL‐99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib‐treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM‐ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib‐included therapeutic regimens may benefit the early response, in‐depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings.

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that primarily arises in the brain, spinal cord, leptomeninges, and vitreoretinal compartment of the eye. The term is sometimes used interchangeably with primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) because DLBCL comprises a great majority (90-95%) of PCNSL. Although rare, other types of lymphomas can be seen in the central nervous system (CNS), and familiarity with these entities will help their recognition and further workup in order to establish the diagnosis. The latter is especially important in the case of PCNSL where procurement of diagnostic specimen is often challenging and yields scant tissue. In this review, we will discuss the most common types of primary lymphomas that can be seen in the CNS with emphasis on the diagnostic histomorphologic, immunophenotypic, and molecular genetic features. The differential diagnostic approach to these cases and potential pitfalls will also be discussed.

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma consisting of large lymphoid cells expressing ALK and CD30. It frequently occurs in patients younger than 30 years. However, this case reports a 90-year-old Japanese woman with ALK+ ALCL. The clinicopathological and genetic results of our case are presented. Although the clinical diagnosis suggested lymphoma with enlarged left supraclavicular and axillary lymph nodes and high levels of soluble interleukin 2 receptors, the initial pathological diagnosis suggested metastasis of undifferentiated carcinoma. This is attributed to the cohesive growth with fibrous stroma and immunohistochemical findings, which were positive for epithelial membrane antigen and negative for leukocyte common antigen. Additional immunohistochemistry revealed positivity for ALK and CD30, and Southern blot analysis demonstrated the rearrangement of T-cell receptor and immunoglobulin genes. Pathologists should include ALCL as a differential diagnosis when epithelial membrane antigen-positive large tumor cells lack pancytokeratins and leukocyte common antigen. Moreover, the occurrence of ALK+ ALCL should not be overlooked in older patients.

A 76-year-old gentleman presented with persistent lower urinary tract symptoms. Multiple biopsies, radiological correlation and ancillary studies were required to achieve a diagnosis. The main differential diagnoses lies between urothelial carcinoma and anaplastic large cell lymphoma (ALCL), both of which are known to be positive for p63 and GATA3. An accurate diagnosis is crucial as the management is significantly different. To avoid misdiagnosis a comprehensive immunohistochemistry panel is necessary. Primary bladder lymphomas are rare. Our case represents the first case of primary ALK-negative TP63-rearranged ALCL. We reviewed the literature and discussed the potential pitfalls for misdiagnosis. [ABSTRACT FROM AUTHOR]

CD30, also known as TNFRSF8 (tumor necrosis factor receptor superfamily member 8), is a protein receptor that is heavily glycosylated inside the Golgi apparatus, as well as a tumor marker that is found on the surface of specific cells in the body, including certain immune cells and cancer ones. This review aims to shed light on the critical importance of CD30, from its emergence in the cell to its position in diagnosing various diseases, including Hodgkin lymphoma, where it is expressed on Hodgkin and Reed–Sternberg cells, as well as embryonal carcinoma, anaplastic large cell lymphoma (ALCL), and cutaneous T-cell lymphoma (CTCL). In addition to its role in positive diagnosis, targeting CD30 has been a promising approach treating CD30-positive lymphomas, and there is ongoing research into the potential use of CD30-targeted therapies for autoimmune disorders. We aim to elaborate on CD30's roles as a tumor marker, supporting thus the hypothesis that this receptor might be the aim of cytostatic treatment. [ABSTRACT FROM AUTHOR]

Aims: The differential diagnosis between ALK-negative anaplastic large cell lymphoma (ALK- ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with high expression of CD30 (CD30high) are essential. However, no reliable biomarker is available in daily practice except CD30. STAT3 is characteristically activated in ALCL. We aimed to investigate whether the status of STAT3 phosphorylation could help the differential diagnosis. Methods: The status of phosphorylation of STAT3 was examined using two antibodies against pSTAT3-Y705 and pSTAT3-S727 by immunohistochemistry in ALK+ ALCL (n=33), ALK- ALCL (n=22) and PTCL, NOS (n=34). Ten PTCL, NOS with diffuse CD30 expression were defined as CD30high PTCL, NOS. Flowcytometric analysis were performed to evaluate the expression of pSTAT3-Y705/S727 in PTCL, NOS (n=3). Results: The median H-scores of pSTAT3-Y705 and S727 were 280 and 260 in ALK+ ALCL, 250 and 240 in ALK- ALCL, and 45 and 75 in CD30high subgroup, respectively. Using H score of 145 as the cutoff value, pSTAT3-S727 alone distinguished between ALK- ALCL and CD30high PTCL, NOS with a sensitivity of 100% and specificity of 83%. Additionally, pSTAT3-S727, but not pSTAT3-Y705, was also expressed by background tumor-infiltrating lymphocytes (S727TILs) in PTCL, NOS. PTCL, NOS patients with high S727TILs H score had a favorable prognosis than those with no TILs (3-year OS rate: 43% vs. 0, p=0.013) or low S727TILs (3-year OS rate: 43% vs. 0, p=0.099). Flowcytometric analysis revealed that of the three patients investigated, two had enhanced pSTAT-S727 signals in neoplastic cell populations, and all three patients were negative for pSTAT3-Y705 expression in both tumor cells and background lymphocytes. Conclusions: pSTAT3-Y705/S727 can be used to help distinguish ALK- ALCL from CD30high PTCL, NOS and pSTAT3-S727 expression by TILs predicts the prognosis of a subset of PTCL, NOS. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) at diagnosis is rare and leads to poor prognosis with the use of the standard ALCL99 protocol alone. CNS-directed intensive chemotherapy, such as an increased dose of intravenous MTX, increased dose of dexamethasone, intensified intrathecal therapy, and high-dose cytarabine, followed by cranial irradiation, has been shown to improve survival in this population. In this paper, the authors describe a 14-year-old male with an intracranial ALCL mass at onset who received CNS-directed chemotherapy followed by 23.4 Gy of whole-brain irradiation. After the first systemic relapse, the CNS-penetrating ALK inhibitor, alectinib, was applied; it has successfully maintained remission for 18 months without any adverse events. CNS-penetrating ALK inhibitor therapy might prevent CNS relapse in pediatric ALK-positive ALCL. Next-generation ALK inhibitors could be introduced as a promising treatment option, even for primary ALCL with CNS involvement, which could lead to the omission of cranial irradiation and avoid radiation-induced sequalae. Further evidence of CNS-penetrating ALK inhibitor combined therapy for primary ALK-positive ALCL is warranted to reduce radiation-induced sequalae in future treatments. [ABSTRACT FROM AUTHOR]

Introduction: BIA-ALCL, a T-cell lymphoma associated with breast implants, poses a growing medical challenge despite its relatively low occurrence, due to the increasing use of implants for cosmetic and reconstructive purposes. Our objective is to review the incidence, characteristics of patients, implant types, management, and outcome of BIA-ALCL. Methods: Pubmed and Science Direct databases were searched to identify case series and observational research. A systematic review was conducted by looking up the keywords "breast implant" and "anaplastic large cell lymphoma". Results: 11 relevant articles were assessed. A total of 353 BIA-ALCL cases have been reported. The mean age at diagnosis was 59.6 years. More than half (53.26%) of the reasons for the breast implants in BIA-ALCL patients were cosmetic. The mean time from breast implant placement to diagnosis was 9.99 years. The majority (71.39%) of documented BIA-ALCL cases have been associated with textured devices. BIA-ALCL patients mainly presented with seroma (54.67%). Outcomes included remission (71%), death because of the disease (4.25%), and recurrence (3.96%) with a mean time of duration of follow-up was 2.53 years. Conclusion: BIA-ALCL is rare cancer in some patients with breast implants but is increasing in incidence largely due to consistent and long-term follow-up. It is important for physicians involved in the care of patients with breast implants to be aware of BIA-ALCL and do routine breast exams. [ABSTRACT FROM AUTHOR]

Breast implant-associated anaplastic large cell lymphoma (breast implant-associated ALCL) is a recently described, distinct clinicopathological entity associated with macrotextured breast implants. The diagnostic workup of a patient suspected to have breast implant-associated ALCL includes cytological assessment of effusions and tissue biopsies of any masses or enlarged lymph nodes, with morphologic and immunophenotypic evaluation and possible flow cytometric and molecular testing. We report the case of a woman found to have breast implant-associated ALCL on fine needle aspirate and core biopsy, who on surgical resection, had extensive local disease with involvement of the resection margins and lymph nodes, requiring systemic treatment. We focus on the flow cytometric findings that identified a population of large cells on the CD30/side scatter dot plot and whose immunophenotype was consistent with breast implant-associated ALCL, highlighting the value of flow cytometry as an adjunct to morphological and immunophenotypic evaluation. [ABSTRACT FROM AUTHOR]

Metallic implant-associated lymphomas are extremely rare. Only seven cases have been reported in association with knee joint arthroplasty, and all tumors were large B-cell lymphomas. This report is the first case of anaplastic large cell lymphoma occurring after total knee replacement arthroplasty. An 80-year-old female patient was admitted because of right knee pain for 2 years. She had undergone total knee replacement arthroplasty 10 years prior. Computed tomography showed an irregular osteolytic lesion in the right lateral femoral condyle, adjacent to the metallic prosthesis. Histologic findings reveal sheets of anaplastic tumor cells that were positive for CD2, CD4, CD5, CD43, and CD30 but negative for CD3, CD20, CD15, and anaplastic lymphoma kinase. Epstein-Barr encoding region in situ hybridization was negative. Analysis of T-cell receptor γ gene rearrangement studies using BIOMED-2–based multiplex polymerase chain reaction confirmed monoclonal T cell proliferation. The woman was finally diagnosed with ALK-negative anaplastic large cell lymphoma.

Shared strategies and correct information are essential to guide physicians in the management of such an uncommon disease as Breast Implant–Associated Anaplastic Large Cell Lymphoma (BIA-ALCL). A systematic review of the literature was performed to collect the most relevant evidence on BIA-ALCL reported cases. A panel of multidisciplinary experts discussed the scientific evidence on BIA-ALCL, and updated consensus recommendations were developed through the Delphi process. The lastest reported Italian incidence of BIA-ALCL is 3.5 per 100.000 implanted patients (95% CI, 1.36 to 5.78), and the disease counts over 1216 cases worldwide as of June 2022. The most common presentation symptom is a late onset seroma followed by a palpable breast mass. In the event of a suspicious case, ultrasound-guided fine-needle aspiration should be the first step in evaluation, followed by cytologic and immunohistochemical examination. In patients with confirmed diagnosis of BIA-ALCL confined to the capsule, the en-bloc capsulectomy should be performed, followed by immediate autologous reconstruction, while delayed reconstruction applies for disseminate disease or radically unresectable tumor. Nevertheless, a multidisciplinary team approach is essential for the correct management of this pathology.

Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) is a rare type of T-Cell (non-Hodgkin's) lymphoma associated with the use of silicone breast implants. Recent widespread awareness has focused not only on the management of this condition but also in regards to potential litigation of surgeons, clinics, and breast implant manufacturers. Allegations of causation and inappropriate patient consent are being raised. The purpose of this article is to establish the timeline of relevant discoveries regarding this condition and associated implications with regards to appropriate informed patient consent.